21-halogen steroids

ABSTRACT

21-halogen steroids having the formula WHEREIN -A-B- is -CH CH- or -CCl CH-, Y and Z are each a halogen atom, and X is a halogen atom having the same or a lesser atomic weight than Y and in the case where -A-B- is a -CCl CH- group, X can also be hydroxyl.

StEItCS P210611: [19] Laurent et al.

[ 51 Feb. 27, 1973 [54] ZI-HALOGEN STEROIDS [73] Assignee: ScheringAktiengesellschaft, Berlin and Bergkamen, Germany 22 Filed: March11,1970

21 Appl.No.: 23,117

[30] Foreign Application Priority Data March 11, 1969 Germany ..P l9 13042.8

Jan. 29, 1970 Germany ..P 20 04 767.0

52] US. Cl. ..260/397.3, 260/397.45, 424/243 [51] Int. Cl. ..C07c 169/34'[58] Field of Search ../Machine Searched Steroids [56] References CitedUNITED STATES PATENTS 3,290,338 12/1966 Shapiro et al. ..260/397.43,364,203

1/1968 Beard et alt ..260/239.5

3,546,215 l2/l970 Fried ..260/239.55

Primary Examiner-Henry A. French Attorney-Michael S. Striker [57]ABSTRACT Zl-halogen steroids having the formula CHGZ --CHa wherein-A--B-- is CH=CH- or CCl=CH-, Y and Z are each a halogen atom, and X isa halogen atom having the same or a lesser atomic weight than Y and inthe case where AB-- is a CCl=CH- group, X can also be hydroxyl.

17 Claims, No Drawings 2 1 -HALOGEN STEROIDS This invention relates to anovel class of halogen steroids having the formula:

CHQZ

t l om wherein the groups AB and Z have "the same meanings as givenabove, halogen or hypohalogeneous acid and in the case where the finaldesired products are 9a-fluoro-2-chloro-l lfi-hydroxysteroids, the 90:-chloroor bromo-l lB-hydroxysteroid of Formula I are converted into thecorresponding 9,11 B-epoxysteroid' and thereafter the epoxy ring issplit with hydrogen fluoride, or

b. exchanging the 2l-hydroxy group of a 2l-hydroxysteroid having theformula:

(III) wherein the groups AB--, X and Y have the same meanings as givenabove, for halogen.

For introducing the halogen atom at the A'"-double bond in accordancewith the procedure set out under (a), there exist a numberofpossibilities. For instance,

halogen, such as chlorine or bromine or combinations thereof, as forinstance, chloromonofluoride or bromomonochloride, or halogen frompolyhalogenides, as for instance, potassium triiodide or iodine benzenedichloride, can be directly attached to the double bond.

Particularly advantageous is the halogen addition where there is addedsimultaneously a positive and a negative halogen atom to the A"-steroid.As reagents which contain positive halogen, there may be mentioned:halogen succinimide, halogen acetamide or the halogens themselves. Asnegative halogen sources, there are suitable, for instance, hydrohalicacid and alkali metal halogenides, preferably lithium halogenide, i.e.,lithium chloride and lithium bromide.

The addition of halogen onto the A -double bond of the steroid iscarried out so that the positively charged halogen adds onto the9-position and the negatively charged halogen is added onto thell-position of the molecule. The atomic weight of the halogen in the9-position because of the known different electronegativities ofhalogens cannot be less than the halogen in the ll-position. The halogenaddition to the W -double bond takes place preferably at temperatures ofbetween C to 50C.

The addition of hypohalous acids to the A -double bond of the compoundhaving Formula II is carried out in accordance with the heretofore knownmethods. A prefer-red method is the treatment of the A -double bond withreagents which in the presence of water and in acid reaction medium actto decompose hypohalous acids and to free the halogen and especiallywith halogen cation forming reagents such as N-chloroor N-bromoacetamideor N-halogenacylimide and most preferably N-bromoor N-chlorosuccinimide.

In the case where it is desired that the final products be 9a-fluorocompounds, then following the halogenhydrine addition to the 9,11-doublebond, using the known procedure, for instance, treatment with basicreagents such as NaOl-I, KOH, I CO potassium acetate, pyridine and thelike, preferably at elevated reaction temperatures, the 9a-bromo- (orchloro-)l 1B- hydroxy group can be closed to form a 9,1 l-oxide ring,which can then be transformed with hydrofluoric acid into the 11B-hydroxy-9a-fluoro group.

The exchange of the 2l-hydroxy group for a halogen atom in accordancewith the process set out at (b) is also carried out by conventionalmethods. A particularly preferred method involves the esterification ofthe 2l-hydroxy group with sulfonic acid, preferably with methanesulfonic acid or p-toluene sulfonic acid and then exchanging thesulfonic acid group for halogen. The esterification of the 21-hydroxygroup takes place for instance by reacting a compound of Formula IIIwith sulfonic acid chloride in the presence of an organic base, forinstance pyridine, or in the presence of aqueous alkali. The exchange ofthe sulfonic acid group for a halogen atom takes place mostadvantageously by reacting a 2l-sulfonic acid ester with analkalihalogenide such as lithium chloride or potassium hydrogen fluoridein the presence of a polar solvent, as for instance dimethyl formamide,at a reaction temperature of 50 to C.

A further method for carrying out the exchange of the 2l-hydroxy groupfor a halogen atom is carried out by reacting a compound of Formula IIIwith a conventional halogenation agent, as for instance, thionylchloride or methane sulfonic acid chloride. This reaction is preferablycarried out with an excess of the halogenating agent in the presence ofan organic base, for instance pyridine, at a reaction temperature below80C.

The new compounds when evaluated by the vasoconstriction test carriedout with male subjects exhibited, following local application, a markedinflammation-inhibiting activity, as can be seen from the table whichfollows, wherein compounds corresponding to Examples 2-7 of theapplication have been compared with the known6a-fluoro-1113,2l-dihydroxy-16a-methyl- 1,4-pregnadiene-3,20-dione(Compound I). These results were most surprising as the compounds ofExamples 2-7 contain no free or esterified hydroxyl groups.

The experimental demonstration of clinical superiority of the compoundsof the invention in the vasoconstrictor test were conducted as follows:On the backs of male experimental subjects (1838 years of age), a markedhyperemia was produced by drawing over the backs of the subjects for 20successive times a 2 cm. wide Tesa film which cut up the stratum comeumof the skin. There was then applied to adesignated 4 cm size fieldwithin the stripped area and under equal application of pressure about50 mg of a water/oil salve base which contained 0.1%, 0.01%, 0.001%respectively of the test substance. The backs of the subjects were thenphotographed at designated time intervals with Kodak colorfilm. Forevaluating the hyperemia and the vasoconstriction, the color of aparticular skin field in the Kodak colorfilm was converted into itscorresponding brightness value. The sections projected from thecolorfilm through a diaphragm onto an interfence filter can bedifferentiated through their brightness. As brightness indicator, therewas used a secondary electronic multiplier and for the estimation of thecolor values, the anode current of the secondary multiplier wasmeasured.

The determination of the vasoconstriction which is representative of theinflammatory syndrome and indicative of the onset of action, degree ofactivity and duration of activity was made by ascertaining the colorvalue of the untreated skin and the treated skin and comparing this withthe color value for the normal skin, wherein the value for normal skinis fixed at 100 and the color value for untreated skin at 0. Small,average and high grade vasoconstriction values fall within the range to100.

0.1 30 65 100 0.01 25 100 0.001 10 40 111. 6a, 21-difluoro- 9,11B-dichloro-16amethyl-1,4- pregnadiene-B,20- dione trifluoro-9-chloro-16a-methyl-l,4 pregnadiene-3,20- dione 0.1 35 80 100 0.01 25 60 1000.001 15 50 80 100 V. 6a,] lfl-difluoro- 2,9,2l-trichloro-I6amethyl-1,4- pregnadiene-3,20- dione 0.1 10 25 60 100 0.01 1020 50 100Vl6a,llfl,21-

trifluoro2,9- dichloro-16amethyl-1,4- pregnadiene-3,20- dione 0.0120 4090 100 0.00110 30 80 90 100 V11 601,2 1 -difluoro- 2,9,1lfl-trichlorol6a-methyl-1,4- pregnadiene- 3,20,dione The values as setout in Table l unequivocally establish that when the compounds of theinvention are used, the onset of anti-inflammatory activity beginsearlier and the desired maximum effect is realized sooner than with thecomparison compound. Further, the intensity of the action of the newcompounds during the period of action is much higher than that of theknown compound.

Further, the high activity of the compounds of the invention is notassociated with any undesirable side effects. Thus, for example, thecarbohydrate change brought about by the compounds of the invention isin general very slight or is not influenced at all. The gluconogeneticactivity is also markedly reduced, as is evidenced by the fact that theblood sugar concentration is not increased and the liver glycogen isonly at extremely high doses affected. The only noticeable changes arethe slight influence on the liver enzyme tryptophane pyrrolase and thetransaminases GOT and GPT. Even less The is the influence on sodium,potassium and phosphate elimination by the active agents in accordancewith the invention.

The compounds of the invention can be combined with the conventionalcarriers and used for making the preparation suitable for treatment. thecompounds can be used (a) locally for contact dermatitis, exzema ofvarious types, neuroderrnatitis, erythrodermatitis, burns Grades 1,pruritis vulvae and ani, rosacea erythematodes cutaneous, psoriasis,lichen ruber planus and verrucosus; (b) orally for acute and chronicpolyarthritis, neuroderrnatitis, bronchial asthma, hay fever, etc.

F. in C l lu 25 CHCL methyl-4,901)-pregnadiene- 3,20-dione oily +l11 e=16100 6a-fluoro-2 l-mesyloxy- 1 6amethy1-1,4,9(l 1)-pregnatriene-3,20-dione 16a-methy1-l,4,9(1 1)- pregnatriene-3,20-dione6a-fluoro-2-chloro-2 1 -mesyloxy- 16a-methyl-l,4,9(1l)-pregnatriene-3,20-dione The preparation of6a-fluoro-2-chloro-2l-hydroxy- 16a-methyll ,4,9( l 1)-pregnatriene-3,20-dione can take place, for example, in the followingmanner:

6a-fluoro-1 lfl-hydroxy-Z1-acetoxy-16a-methyl-l,4-pregnadiene-3,20-dione was reacted at C in tetrahydrofuran withN-chloro-succinimide and hydrogen chloride. There was formed6a-fluoro-2- chloro-l l B-hydroxy-Zl-acetoxy-16a-methy1-1,4-pregnadiene-3,20-dione (m.p. 207-209C) which was converted into6a-fluoro-2-chloro-21-acetoxy-16amethy1-l,4,9( 1 1)-pregnatriene-3,20-dione (mp. 161-162C) by heating with methanesulfochloride in pyridine-d1methylformamide. The saponification of the21-acetate is carried out by dissolving the dione in methylene chlorideand treating the solution with dilute methanolic soda lye.

The following Examples are given in order to illustrate the inventionand are not to be construed as in any way limiting the scope thereof.

EXAMPLE 1 3.4 m1 HClsaturated dioxan. After a 40 minute reaction period,the mixture was poured into sodium sulfate containing water, theprecipitated product taken off with suction, washed, dried and chromato-5 graphed on silica gel. 3.5-8 percent acetone-pentane eluted 2.49 g6a-f1uoro-9,l1B-21-trich1oro-16amethyl-l,4-pregnadiene-3,20-dione havinga melting point of 237239C (acetone-hexane); [04 0 180; 623 15300. 10

EXAMPLE2 2 ml anhydrous hydrogen fluoride, 3 ml tetrahydrofuran, 4 m1methylene chloride and 2g N- chlorosuccinimide were reacted at 50C. 1.0g 6afluoro-21-ch1oro-16a-methyl-1,4,9( l 1)-pregnatriene- 3,20-dionewere dissolved in this mixture and then stirred for 30 minutes at 0C.The resultant mixture was then poured into icewater which containedsodium hydrogen carbonate and sodium sulfate. The material whichprecipitated out was suctioned off, dried and chromatographed on silicagel. 10.3-11.5 percent acetone-pentane eluted 265 mg 601-11,8-diflu0ro-9,21-

dichlorol a-methyl-l ,4-pregnatriene-3 ,20-dione having a melting pointfo 240.5 -242C(acetone-hexane);

[a] n= 137; UV: e 15 ,500.

EXAMPLE 3 2.2 g 6a,21-difluoro-l6a-methyl-1,4,9(11)pregnatriene-3,20-dione (m.p. 230-232.5[a] +51; 2 g=l 6,400) werereacted with N-chlorosuccinimide and lithium chloride as set out inExample 1. The crude product was chromatographed. 1.4-2.2 percentacetone-methylene chloride eluted 1.17 g 601,21- difluoro-9,11,8-dich1oro-16a-methyl-l ,4-pregnadiene- 3,20 -dione having a meltingpoint of 226-227.5C (acetone-hexane); [a] =172; UV: 6236 15,500.

EXAMPLE 4 2.0 g 6a,21-difluoro-16a-methy1-1,4,9(1 1pregnatriene-3,20-dione was reacted with N-chlorosuccinimide andhydrogen fluoride as set out in Example 2. The crude product waschromatographed. 3.8-5 percent acetone-pentane eluted 1.20 g 601,1113,21- trifluoro-9-chloro-1a-methyl-l,4-pregnadiene-3 ,20- dione havinga melting point of ZZZ-225C (acetonehexane); [a] ,,=+l27; UV: e,;-l6,l00.

EXAMPLE 5 g 6a-fluoro-21-ch1oro-16a-methyl-4,9( 1 1pregnadiene-3,20-dione (mp. 145-146C; [01 0 +142; e 16,500) was reactedwith N-chlorosuccinimide and hydrogen fluoride as set out in Example 2.The crude product was chromatographed. 9.1-10 percent acetone-pentaneeluted 1.33 g 601,1 1B82 difluoro-9,2 l-dichlorol 6a-methyl-4-pregnene-3,20- dione having a melting point of 236-237C (acetone- 60 hexane); [a]=+l 70; UV: e =l6,500.

EXAMPLE 6 A solution of 2.7 g 611, 20-difluoro-2-chloro-16amethyl-1, 4,9(11)-pregnatriene-3, 20-dione (m.p. 169-17l[a] +10"; e 15,400) in 110m1 dioxan and 27 ml water were reacted with 11g N- chlorosuccinimide andl 1 m1 7 percent perchloric acid.

After an hour the reaction mixture was stirred into sodium sulfatecontaining icewater. The precipitated EXAMPLE 7 2.0 g 6or-fluoro-2,2 1-dichloro- 1 6a-methyl- 1 ,4,9 (11)-pregnatriene-3,20-dione (m.p.l85l87C; [011 +29; e 15,700) were introduced into chlorohydrin asdescribed in Example 6. The crude product was crystallized out ofacetone-hexane and yielded 1.30 g 6a-fluoro-2,9,2l-trichloro-l 1B-hydroxy- 16a-methyl-l ,4-pregnadiene-3,20-dione having a melting pointof 238-239.5[a] =+132 (chloroform); UV: e 15,500 (methanol).

EXAMPLE 8 2.2 g 6a-fluoro-2,2 l-dichloro- 1 6a-methy1- 1 ,4,- 9( 1 l)-pregnatriene-3,20-dione, 4.4 g N-bromosuccinimide and 4.4 ml 70percent perchloric acid in 88 ml dioxan and 22 ml water were stirredtogether at room temperature for hours. The reaction product wasprecipitated out of icewater containing sodium sulfate, washed, driedand chromatographed on silica gel. 12-15 percent acetone-pentane eluted1.32 g 60:- fluoro-2,2l-dichloro-9-bromo-llB-hydroxy-l6amethyl-l,4-pregnadiene-3,20-dione having a melting pointof 217-219C (acetone-hexane); [01], +1 17 (chloroform); UV: e 14,200(methanol).

EXAMPLE 9 l 1.3 g 6a-fluoro-2,21-dichloro-9-bromo-l 1B-hydroxy-l6a-methyl-l,4-pregnadiene-3,20-dione and 14.7 g potassiumacetate in 300 ml ethanol were heated under reflux for 2 hours.Following cooling, water was introduced, the precipitated product takenoff with suction, washed, dried and chromatographed on silica gel. -13percent acetone-pentane eluted 2.99 g 611- fluoro-2,21-dichloro-9,1IB-epoxyl 6a-methyl-9B- pregna-l ,4-diene-3,20-dione having a meltingpoint of 125-128[a] +58 (chloroform); UV: e 14,300 (methanol).

EXAMPLE 10 3.0 g 6a-fluoro-2,2l-dichloro-9,l1B-epoxy-l6amethyl-9B-pregna-1,4-diene-3,20-dione were dissolved at -50Cin a mixture of l 1 ml hydrogen fluoride and 10 ml dimethylformamide andallowed to stand for 4 days at 0C. The reaction mixture was then stirredinto sodium hydrogen carbonate containing water, the precipitatedmaterial taken off with suction and dissolved in methylene chloride. Thesolution was washed with water, dried and evaporated in vacuo. Theresidue was chromatographed on silica gel. 22-23 percent acetone-pentaneeluted 986 mg 6a,9-difluoro-2,2l dichloro-l 1B-hydroxyl 6a-methyl-l,4-pregnadiene- 3,20-dione having a melting point of 182-183C(diisopropyl-ether; [111 +100 (chloroform); UV: s 14,800 (methanol).

EXAMPLE 11 4.5 g 601,2 1 -difluoro-2-chlorol 6a-methyl- 1 ,4,9l1)-pregnatriene-3,20-dione in 225 m1 concentrated acetic acid werereacted with 4.5 g N-chlorosuccinimide, 22.5 g lithium chloride and 4.5ml l-lCl saturated dioxan and stirred for 1 hour at room temperature.The reaction mixture was poured into sodium sulfite containing water andthe precipitated material isolated. The recovered material waschromatographed on silica gel. The yield amounted to 1.96 g of6a,2l-difluoro- 2,9,1 lB-trichloro-l6a-methyl-1,4-pregnadiene-3,20-dione having a melting point of 243-246C (methylene chloride-acetone);[M +137 (chloroform); UV: 6 15,500 (methanol).

EXAMPLE 12 A solution of 2.2 g 601,2l-difluoro 2-chloro-l6amethyl-l,4,9(1 l )-pregnatriene-3,20-di0ne in 4.4m] anhydrous hydrogen fluoride, 6.6ml tetrahydrofuran and 8.8 ml methylene chloride were reacted at 50Cwith 4.4 g N-chlorosuccinimide. After a 16-hour reaction period, thereaction mixture was poured into water containing sodium hydrogencarbonate and sodium sulflte at 0C. The precipitated material wassuctioned off, dissolved in methylene chloride, the solution washed withwater, dried and concentrated in vacuo. The residue was chromatographedon silica gel. 12-15 percent acetone-hexane eluted 453 mg 601,113,21-trifluoro-2,9-dichloro-l6a-methyl-1,4-pregnadiene- 3,20-dione having amelting point of 249250C (acetone-hexane); [a] D=+86 (chloroform); UV: c15,600 (methanol).

EXAMPLE 13 2.0 g 6a-fluoro-2,2 l-dichloro-l 6a-methyl-l ,4,9(1l)-pregnatriene-3,20-dione were reacted with N- chlorosuccinimide andlithium chloride as described in Example 1 1. The crude product waschromatographed. The yield amounted to 692 mg 6oz-fluoro-2,9,1 18,21-tetrachlorol 6a-methy1- 1 ,4-pregnadiene-3,20--dione having a meltingpoint of 250252C (acetone-hexane); [M +142 (chloroform); UV: e 15,500(methanol).

EXAMPLE 14 2.0 g 6a-fluoro-2,2 l-dichloro-l 6a-methyll ,4,9(l1)-pregnatriene-3,20-dione were reacted with N- chlorosuccinimide andhydrogen fluoride as described in Example 12. The crude product waschromatographed. 8-9 percent acetone-pentane eluted 367 mg 601,1lB-difluoro-2,9,2l-trichloro-l6a-metl1yl-1,4- pregnadiene-3,20-dionehaving a melting point of 232-237[a] +l03 (chloroform); UV: e 15,500

EXAMPLE 15 A solution of 3.0 g6a-fluoro-2-chloro-2l-acetoxyl6a-methyl-1,4,9( 1l(-pregnatriene-3,20-dione in 120 ml dioxan was reacted with 30 mlwater, 12 g N- chlorosuccinimide and 12 in] percent perchloric acid andstirred for an hour at room temperature. The reaction mixture was pouredinto water containing sodium sulfite, the precipitated product suctionedoff,

washed, dried and chromatographed on silica gel. 2.3-4.3 percent acetonemethylene chloride eluted 1.23 g6a-fluoro-2,9-dichloro-1la-hydroxy-Zl-acetoxy-l6a-methyl-1,4-pregnadiene-3,20-dione having a melting point of l20-121C (methanol); {a1 +104(chloroform); UV: e 14,800 (methanol).

1.20 g 6a-fluoro-2,9-dichloro-l 1B-hydroxy-21- acetoxy-16a-methyl-1,4-pregnadiene-3,20-dione were dissolved in 25 ml methylene chloride. 24ml methanolic 0.2N potassium hydroxide solution were introduced andstirring continued for 10 minutes at room temperature under nitrogen.The reaction mixture was diluted with methylene chloride, washed toneutrality with water, dried and concentrated in vacuum. The residue waschromatographed. 11-l3.5 percent acetonemethylene chloride eluted 480 mg60z-fluoro'2,9- dichloro-l 16,2 l-dihydroxy- 1 a-methyl-l ,4-pregnadiene-3,20-dione having a melting point of 249250C (methylenechloride); ldl n=+95 (chloroform); UV: E145: 15,200 (methanol).

450 mg 6a-fluoro-2,9-dichloro-l 113,2 l-dihydroxy-16a-methyl-l,4-pregnadienes3,20-dione were dissolved in 10 ml abs.pyridine, the solution reacted with 2 ml methane-sulfonic acid chlorideand under exclusion of moisture stored for 16 hours at room temperature.The resulting mixture was diluted with methylene chloride, the methylenechloride phase washed with dilute sulfuric acid and water, dried andconcentrated in vacuum. The residue was chromatographed on silica gel.There was obtained 110 mg 6a-fluoro-2,9,21- trichloro-l 1 B-hydroxyl6a-methyl- 1 ,4-pregnadiene- 3,20-dione having amelting point of237-239C (acetone-hexane); [111 +132 (chloroform); UV: e 15,6000(methanol).

EXAMPLE 16 6.2 g 601,2 1 -difluoro-2-chloro- 1 6a-methyl-1,4,9(11)-pregnatriene-3,20-dione were, as set out in Example 8,converted with bromohydrin. The crude product was chromatographed onsilica gel. 13-18 percent acetone-pentane eluted 2.30 g6a,2l'-difluoro-2- chloro-9-bromo-l l B-hydroxyl 6a-methyl-l ,4-pregnadiene-3,20-dione having a melting 7 point of 203-211 C (acetoiiehexane); a] +10' (chloroform); UV: em 14,200 (methanol).

EXAMPLE 17 2.2 g 601,2l-difluoro-2-chloro-9-bromo-1IB-hydroxy-l6a-methyl-l,4-pregnadiene-3,20-dione were, as set out inExample 9, converted into the epoxide. The crude product waschromatographed on silica gel. 8-9 percent acetonehexane eluted 1.02 g6a,2l-difluoro-2- chloro-9,l lB-epoxy-16a-methyl-9/3-pregna'1 ,4-diene-3,20-dione having a melting point of 192-194C (Acetone-hexane); [a +43(chlorofo I E253 (methanol).

EXAMPLE 18 -dione having a melting point of 194-l99C. [11] 64(chloroform), UV: 14,500 (methanol).

We claim: 1. 2 l-halogensteroids having the formula wherein -A-B- is amember selected from the group consisting of --CH=CH- and -CCl=Cl-l-, Yand Z are each a halogen atom and X is a halogen atom having the same ora lesser atomic weight than Y and in the case where A--B- represents-CC1=CH, then X can also be hydroxy.

2. 2l-halogensteroids according to claim 1, wherein -A-B- is and-Cl-1=CH, Y and Z are each a halogen atom and X is a halogen atom havingthe same or a lesser atomic weight than Y.

3. 21-halogensteroids according to claim 1, wherein -A-B is CC1=CH, Yand Z are each a halogen atom and X is a halogen atom having the same ora lesser atomic weight than Y, and X can also be hydrox- 4. 21-halogensteroid according to claim 1 designated 6a-fluoro-9,l 113,2 1-trichloro-l 6a-methyl- 1,4-pregnadiene-3 ,20-dione.

5. 21-halogen steroid according to claim 1 designated 601,1lB-difluoro-9,2 l -dichlorol 6a-methyl- 1 ,4-pregnadiene-3,20-dione.

6. 21-halogen steroid according to claim 1 designated 601,2 1-difluor0-9,1 1B-dichloro-16a-methyll ,4-pregnadiene-3,ZO-dione.

7. 2l-halogen steroid according to claim 1 designated 6a,113,21-trifiuoro-9-chloro-l6a-methyl- 1 ,4-pregnadiene-3 ,20-dione.

8. 2l-halogen steroid according to claim 1 designatedv 601,21-difluoro-2,9-dichloro-l lB-hydroxy- 16a-methyl-l,4-pregnadiene-3,20-dione.

9. 2l-halogen steroid according to claim 1 designated 6a-fiuoro-2,9,2 1-trichloro-1 lB-hydroxyl 6 a-methyl-l ,4-pregnadiene-3 ,20-dione.

l0. 2l-halogen steroid according to claim 1 designated6a-fluoro-2,21-dichloro-9-bromo-l 13- hydroxy- 1 6a-methyl-l,4-pregnadiene-3 ,20-dione.

l1. 21-halogen steroid according to claim 1 designated 6a,9-difluoro-2,2l-dichloro-l IB-hydroxy- 16oz-methyl-l ,4-pregnadiene-3 ,20-dione.

12. 2l-halogen steroid according to claim 1 designated601,21-difluoro-2-chloro-9-bromo-l 1B- hydroxyl 6a-methyll,4-pregnadiene-3,20-dione.

l3. 2l-ha1ogen steroid according to claim 1 designated 6019.2l-trifluoro-2-chloro-l IB-hydroxy- 1 a-methyll ,4-pregnadiene-3,2-dione.

l4. 2l-halogen steroid according to claim 1 designated 601,21-difluoro-2,9, 1 1B-trichloro-16amethyl-l ,4-pregnadiene-3,20-dione.

15. ZI-halogen steroid according to claim 1methyl-l,4-pregnadiene-3,20-dione. designated6a,l13,21-trifluoro-2,9-dichloro-16a- 17. 2l-hal0gen steroid accordingto claim 1 methyl-l ,4-pregnadiene-3 ,ZO-dione. designated 601,1lB-difluoro-2,9,2 l -trichloro- 1 6a- 16. 2l-halogen steroid accordingto claim 1 y A'P' designated 6a-flu0ro-2,9,llB,2l-tetrachloro-l6a-

2. 21-halogensteroids according to claim 1, wherein -A-B- is and -CHCH-, Y and Z are each a halogen atom and X is a halogen atom having thesame or a lesser atomic weight than Y.
 3. 21-halogensteroids accordingto claim 1, wherein -A-B is -CC1 CH-, Y and Z are each a halogen atomand X is a halogen atom having the same or a lesser atomic weight thanY, and X can also be hydroxy.
 4. 21-halogen steroid according to claim 1designated 6 Alpha -fluoro-9,11 Beta ,21-trichloro-16 Alpha-methyl-1,4-pregnadiene-3,20-dione.
 5. 21-halogen steroid according toclaim 1 designated 6 Alpha , 11 Beta -difluoro-9,21-dichloro-16 Alpha-methyl-1,4-pregnadiene-3,20-dione.
 6. 21-halogen steroid according toclaim 1 designated 6 Alpha , 21-difluoro-9,11 Beta -dichloro-16 Alpha-methyl-1,4-pregnadiene-3,20-dione.
 7. 21-halogen steroid according toclaim 1 designated 6 Alpha , 11 Beta ,21-trifluoro-9-chloro-16 Alpha-methyl-1,4-pregnadiene-3,20-dione.
 8. 21-halogen steroid according toclaim 1 designated 6 Alpha , 21-difluoro-2,9-dichloro-11 Beta-hydroxy-16 Alpha -methyl-1,4-pregnadiene-3,20-dione.
 9. 21-halogensteroid according to claim 1 designated 6 Alpha-fluoro-2,9,21-trichloro-11 Beta -hydroxy-16 Alpha-methyl-1,4-pregnadiene-3,20-dione.
 10. 21-halogen steroid according toclaim 1 designated 6 Alpha -fluoro-2,21-dichloro-9-bromo-11 Beta-hydroxy-16 Alpha -methyl-1, 4-pregnadiene-3,20-dione.
 11. 21-halogensteroid according to claim 1 designated 6 Alpha,9-difluoro-2,21-dichloro-11 Beta -hydroxy-16 Alpha-methyl-1,4-pregnadiene-3,20-dione.
 12. 21-halogen steroid according toclaim 1 designated 6 Alpha ,21-difluoro-2-chloro-9-bromo-11 Beta-hydroxy-16 Alpha -methyl-1,4-pregnadiene-3,20-dione.
 13. 21-halogensteroid according to claim 1 designated 6 Alpha9,21-trifluoro-2-chloro-11 Beta -hydroxy-16 Alpha-methyl-1,4-pregnadiene-3,2-dione.
 14. 21-halogen steroid according toclaim 1 designated 6 Alpha ,21-difluoro-2,9,11 Beta -trichloro-16 Alpha-methyl-1,4-pregnadiene-3,20-dione.
 15. 21-halogen steroid according toclaim 1 designated 6 Alpha ,11 Beta ,21-trifluoro-2,9-dichloro-16 Alpha-methyl-1,4-pregnadiene-3,20-dione.
 16. 21-halogen steroid according toclaim 1 designated 6 Alpha -fluoro-2,9,11 Beta ,21-tetrachloro-16 Alpha-methyl-1,4-pregnadiene-3,20-dione.
 17. 21-halogen steroid according toclaim 1 designated 6 Alpha ,11 Beta -difluoro-2,9,21-trichloro-16 Alpha-methyl-1,4-pregnadiene-3,20-dione.